Patients with invasive lobular carcinoma carrying pathogenic variants in moderate- to high-risk breast cancer predisposition genes may have a greater likelihood of early breast cancer recurrence compared with those without the variants. Polygenic risk scores may not be associated with recurrence risk or clinical outcomes, suggesting that multigene panel testing—but not currently available polygenic risk scores—could identify a subset of patients at higher risk of relapse.
In a prospective longitudinal cohort study at the European Institute of Oncology, researchers enrolled 414 White female patients with primary invasive lobular carcinoma between May 2022 and January 2025. The patients underwent next-generation sequencing using a 113-gene hereditary cancer panel. The primary outcome was breast cancer–free survival, defined as the time from surgery to ipsilateral recurrence, contralateral breast cancer, distant metastasis, or breast cancer–related mortality. Secondary outcomes included overall survival and the prognostic value of eight published polygenic risk score models.
Pathogenic variants were identified in 11% (n = 46) of the patients, including 5% (n = 20) who carried variants in moderate- to high-risk breast cancer predisposition genes, including ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, and NF1. No statistically significant differences were observed between carriers and noncarriers in clinicopathologic characteristics, family history, surgical treatment, or adjuvant therapy.
During a median follow-up of about 3 years, 55% (n = 11) of the patients carrying moderate- to high-risk variants experienced a breast cancer event compared with about 12% (n = 47/394) of the patients without the variants. Five-year breast cancer–free survival was 62% among variant carriers vs. 92% among noncarriers, representing nearly a fourfold greater likelihood of recurrence. Kaplan-Meier analyses similarly demonstrated shorter recurrence-free survival in the variant carrier group.
The researchers found that polygenic risk scores did not improve prognostic stratification. There were no statistically significant differences in polygenic risk scores between the germline variant groups, and the scores were not associated with breast cancer–free survival across score quartiles. Currently available polygenic risk scores did not provide prognostic value in patients with invasive lobular carcinoma, according to the researchers.
Exploratory subgroup analyses suggested that the association between moderate- to high-risk germline variants and recurrence was evident among patients with early-stage disease but not among those with locally advanced disease. Additional analyses also showed shorter recurrence-free survival among carriers of high-penetrance genes compared with patients without moderate- to high-risk variants. The researchers cautioned that these subgroup findings should be interpreted carefully because of the limited number of events.
Although the study represented one of the largest single-center cohorts of patients with invasive lobular carcinoma undergoing multigene panel testing, just 20 patients carried moderate- to high-risk pathogenic variants, limiting the precision of subgroup analyses. The short follow-up of just over 3 years may not have captured the late recurrences typical of hormone receptor–positive invasive lobular carcinoma. Additional limitations included the single-center design, enrollment of only White female patients, and use of polygenic risk score models not specifically developed for invasive lobular carcinoma.
Overall, the findings suggested that multigene panel testing may identify a subset of patients with invasive lobular carcinoma who are at increased risk for early relapse, whereas currently available polygenic risk scores did not demonstrate prognostic utility in this setting.
“Our findings suggest the existence of a distinct subset of [invasvie lobular carcinoma] characterized by germline [pathogenic variants] in [breast cancer]–predisposition genes, which may be associated with an increased risk of early locoregional or distant relapse,” wrote lead study author Giovanni Corso, MD, PhD, of the Division of Breast Surgery at the European Institute of Oncology at the IRCCS in Italy, and colleagues.
Full disclosures of the study authors can be found in the study.
Source: JAMA Network Open
